Glioblastoma Multiforme is a lethal cancer with devastating prognosis. Glioblastoma affects 5-8 persons per 100,000 population. Even using the most aggressive therapeutic approaches, which include, surgical resection of tumor mass, radiation therapy and chemo intervention, median survival term is less than 15-months. The high recurrence of this cancer is due to remnant reservoir of stem cells (Glioma Stem Cells: GSC) that renew the tumor after resection. Therefore, there is urgent unmet need to develop novel targeted therapeutics for Glioblastoma that target critical molecular mediators in its reservoir of stem like cells. Results of our preliminary studies drive this proposal. In preliminar studies, we have formulated novel stabilized and targeted nanoparticles for delivery of dual disease specific siRNAs to Glioblastoma stem like cells. Our nanoparticles carry specific targeting moieties that can readily cross the blood brain barrier and home-in to Glioblastoma cells. Using these nanoparticles we propose to deliver siRNAs to repress molecular mediators critical for tumor progression and self-renewal. Use of siRNA to target most critical mediators expressed in GBM stem like cells ensures reduction of tumor burden to increase patient survival. The dual targeted Nanoparticle therapeutics will be tested in our mouse model of primary human Glioblastoma. Completion of this Phase I preclinical proposal would successfully advance toward Phase II, with the final goal of initiating a clinical trial for patients with Glioblastoma.